Hypersensitivity + Coombs test Flashcards
Define Hypersensitivity
Antigen-specific immune responses that are either Inappropriate or Excessive and result in Harm to Host
What are the 2 types of triggers of Hypersensitivity?
- Exogenous Antigens (infectious microbes, Drugs, Non infectious substances)
- Intrinsic Antigens (Self antigens, infectious microbes)
List and describe the 4 broad types of Hypersensitivity reactions
Type I: Immediate Allergy (IgE driven, mast cell degradanulation)
Type II: Antibody mediated
Type III: Immune complex mediated
Type IV: Cell mediated- Delayed
What are the 2 phases of Hypersensitivity reactions?
Sensitisation phase;
- First encounter with antigen, Activation of APCs and Memory effector cells
Effector phase;
- Pathological reaction upon re-exposure to same antigen
List 5 treatments for Type I Hypersensitivity reactions
- Allergen desensitisation
- Anti-IgE antibodies
- Antihistamine
- LTRA
- Corticosteroids
For Type II Hypersensitivity reactions, state the;
- Time taken to develop
- Antibodies involved
- Targets
- Develops within 5-12 hours
- Involves IgM/ IgG antibodies
- Targets are cell surface antigens
(Exogenous cell surface antigens: A/B, Rhesus D antigens)
(Endogenous cell surface antigens: Self antigens)
What are 2 different types of outcomes of a Type II Hypersensitivity reaction
- Tissue/ cell damage
- Physiological change
List the 2 mechanisms that can lead to Tissue/ Cell damage in a Type II Hypersensitivity reaction
- Complement activation
- Antibody-dependent cell cytotoxicity (Natural Killer cells)
List the 3 processes involved in Complement Activation
- Cell lysis
- Neutrophil recruitment/ activation
- Opsonisation
List 7 Type II Hypersensitivity reactions
- ABO Transfusion reaction
- Haemolytic Disease of the Newborn (HDN)
- Graves’
- Autoimmune Haemolytic Anaemia
- Myasthenia Gravis
- Goodpasture’s
- Immune Thrombocytopenic Purpura
Which blood groups are universal PLASMA and BLOOD donors?
PLASMA: AB (lack A and B antibodies)
BLOOD: O (lack A or B antigens)
Describe the immune mechanism of ABO/ Haemolytic Transfusion Reactions
- Incompatibility in ABO or Rhesus D antigens
- Donor RBC destroyed by Recipient’s Immune system
- RBC lysis induced by Type II Hypersensitivity, involving natural IgM antibodies
List 4 consequences of ABO/ Haemolytic Transfusion reaction
- Shock
- Kidney failure
- Circulatory collapse
- Death
What does Rh (+ve) blood mean?
Presence of D antigen on RBCs
Describe the immune mechanism of Haemolytic Disease of the Newborn (HDN)
- In Rh (-ve) pregnant woman, baby carries Rh (+ve) blood, so small amounts of D-positive RBCs enter maternal circulation
- Mother produces anti-D IgG antibodies. In future pregnancies, these IgG ABs cross Placenta
- Maternal anti-D IgGs attach to foetal RBCs if they are Rh (+ve)
- RBCs with attached ABs are cleared by Liver and Spleen macrophages
How is HDN prevented?
Rh (-ve) pregnant women are given a small amount of Rh Immunoglobulin/ RhoGAM.
This prevents formation of their own anti-D antibodies
Describe the clinical features of a baby born with HDN
- RBC destruction causes elevation of Bilirubin in Foetal blood
- After birth Bilirubin is no longer cleared by Placenta, so Bilirubin accumulates-> Jaundice
What is the main complication of increased Bilirubin levels for the baby?
- Bilirubin may enter the brain to cause Kernicterus.
- This can be fatal and leaves permanent neurological damage in surviving babies
Why does an ABO mismatch rarely cause HDN?
The naturally occurring Anti-A/ Anti-B antibodies are IgM, so DO NOT cross the placenta
List the 2 mechanisms that can lead to Physiological Change in a Type II Hypersensitivity reaction?
For each mechanism, suggest a disease that it causes
Receptor stimulation;
- Graves’ disease
- (Increased thyroid activity, Antigen= TSH receptor)
Receptor blockade;
- Myasthenia Gravis
- (Impaired neuromuscular signalling, Antigen= AChR)
List 4 therapeutic approaches to Tissue/ Cell damage in a Type II Hypersensitivity reaction
- Anti-inflammatory drugs (complement activation)
- Plasmapheresis (ABs and inflammatory mediators)
- Splenectomy (Opsonisation/ phagocytosis)
- IV Immunoglobulin/ IVIG (IgG Degradation)
Suggest 2 therapeutic approaches to Physiological change in a Type II Hypersensitivity reaction
- Correct metabolism (for receptor stimulation e.g antithyroid drugs)
- Replacement therapy (for receptor blockade e.g Pyridostigmine in Myasthenia Gravis)
For Type III Hypersensitivity, state the;
- Time taken to develop
- Antibodies involved
- Targets
- Cause of tissue damage
- Develops in 3-5 hours
- Immune complexes (between antigens and IgM/IgG)
- Targets soluble antigens (Foreign or Endogenous)
- Deposition of immune complexes in tissues
List 3 key factors that affect Immune Complex pathogenesis in Type III Hypersensitivity
- Complex size (Small+large ICs cleared easily, Intermediate ICs very hard to clear)
- Host response (Low affinity antibody, Complement deficiency)
- Local tissue factors (Haemodynamic and Physiochemical factors)
In Type III Hypersensitivity, persistence of Immune Complex deposition drives the disease.
List 4 common systems affected
- Joints
- Skin
- Small vessels
- Kidney
List 3 diseases caused by Type III Hypersensitivity
- RA (Antigen= Anti-rheumatoid Factor IgG/ Fc portion of IgG)
- Glomerulonephritis (Infectious)
- Lupus/ SLE (Antigen= dsDNA, more common in Females, can cause repeated miscarriages)
Describe the immune mechanism of a Type III Hypersensitivity reaction
- Intermediate ICs deposited in tissue
- Complement activated
- Neutrophil chemotaxis
- Neutrophil adherence and degranulation
For Type IV Hypersensitivity, state the;
- Time taken to develop
- Antibodies involved
- 3 types of response to Exogenous antigens
- Develops within 24-72 hours
- Involves Lymphocytes and Macrophages (TH1 cells)
Three types;
- Contact Hypersensitivity
- Tuberculin Hypersensitivity
- Granulomatous Hypersensitivity
Describe the duration and outcome of Type IV Contact Hypersensitivity
Duration: 48-72 hours
Outcome: Epidermal reaction
Describe the duration and outcome of Type IV Tuberculin Hypersensitivity
Duration: 48-72 hours
Outcome: Dermal reaction (Induration and swelling)
Describe the duration and outcome of Type IV Granulomatous Hypersensitivity
List 4 examples
Duration: 21-48 days
Outcome: Tissue damage
- Sarcoidosis
- TB
- Leprosy
- Schistosomiasis
List 3 diseases caused by a Type IV Hypersensitivity response to Endogenous antigens
- RA
- Hashimoto’s
- Insulin dependent DM (Type 1)
Describe the treatment options for Type III and IV Hypersensitivity
- Monoclonal antibodies
Anti-inflammatory drugs;
- NSAIDs
- Corticosteroids
- Steroid sparing agents (Azathioprine, Mycophenolate Mofetil, Cyclophosphamide)
Which drug is used to treat Myasthenia Gravis and how does it work?
Pyridostigmine: Is an AChesterase Inhibitor, so increases synaptic concentration of ACh.
This prolongs the action of ACh, so greater chance of APs ocuring the muscle, leading to contraction
Type I Hypersensitivity is Allergy. Compare the 2 types of Immediate Reaction
Local: Ingested/ inhaled antigen
Systemic: Insect sting/ IV administration
(Allergens are environmental, non-infectious agents)
List the 3 types of allergen exposure
- Seasonal (pollen)
- Perennial (throughout year) (animal dander, dust mite)
- Accidental (Insect venom, Drugs, Chemicals, Food)
Describe the 2 mechanisms of Type I Hypersensitivity
- Mast cell activation
Abnormal adaptive response against allergen’
- Activation of TH2 cells
- Release of IL-4, IL-5, IL-13
- IgE production
Development of allergy can be influenced by Genetics and Environmental Exposure.
What are 2 reasons allergies are more prevalent in developed countries?
- Reduced infection burden
- Microbial Dysbiosis (Alteration of the symbiotic relationships with parasites and bacteria)
What is the Hygiene Hypothesis?
Children exposed to animals, pets and microbes in the early post-natal period appear to be protected against certain allergic diseases
Describe the strategic location of Mast cells
- In most Mucosal and Epithelial tissues (GI, Skin, Respiratory epithelium)
- In Connective Tissue surrounding RBCs
List 5 Mast cell mediators
- Tryptase (Remodels CT matrix)
- Histamine
- Platelet Activating Factor
- Leukotrienes (C4, D4, E4)
- Interleukins 4,5,13
State the biological effects of Histamine and Leukotrienes
- Increased vascular permeability
- Cause smooth muscle contraction
State the biological effects of Platelet Activating Factor
- Attracts Leukocytes
- Activates Neutrophil, Eosinophils and Platelets
Describe the immune mechanism of allergic reaction
- 1st exposure to allergen;
- TH2 response and allergen-specific IgE produced
- Allergen-specific IgE binds to Mast cell via FcεRI (high affinity IgE receptor) - 2nd exposure;
- Allergen will cross link with 2 IgEs
- Causes activation of Mast Cells-> Degranulation
Describe Mast cell degranulation (mediators released and biological effects)
- Release of Histamine and Leukotrienes
Causes;
- Increased vascular permeability
- Vasodilation
- Bronchial constriction
What causes Urticaria?
What are the mediators involved?
- Mast cell activation in Epidermis
- Histamine and Leukotrienes/ Cytokines
With prolonged + chronic exposure, what can Urticaria develop into?
- Atopic dermatitis
- Eczema
What causes Angioedema?
What mediators are involved?
- Mast cell activation in deep dermis
- Histamine and Bradykinin
List 5 systemic effects of Mast cell activation (Anaphylaxis)
- Hypotension
- CVS collapse
- Generalised Urticaria
- Breathing problems
- Angioedema
State the treatment of Anaphylactic shock and list ways it helps
- IM Adrenaline (absorbed, works better than SC)
- Reverses peripheral vasodilation, Reduces oedema, Alleviates hypotension
- Reverses Airway Obstruction/ Bronchospasm
- Increases the force of Myocardial Contraction
- Inhibits Mast cell activation
When treating Anaphylaxis, how many adrenaline doses are needed?
May need multiple
Of the 5 available therapies for Type I Hypersensitivity, which 3 target Mast cel activation
- Antihistamines
- LTRAs
- Corticosteroids
What are the 2 types of Coombs test?
- Direct Coombs test/ Direct Antiglobulin test (DAT)
- Indirect Coombs test/ Indirect Antiglobulin test (IAT)
Compare the uses of the Direct and Indirect Coombs test
DAT;
- Looks directly at RBCs
- Used to detect Autoimmune Haemolytic Anaemia
IAT;
- Looks at plasma
- Used to check Compatibility of Donor blood AND to see if maternal blood contains ABs that may harm baby
How does the Direct Coombs test work?
Positive result if Coombs’ Reagent ABs bind to ABs that are already attached to RBC antigens
How does the Indirect Coombs test work?
Looks for unattached ABs in plasma
